Previous work to elucidate the underlying molecular mechanisms of esophageal carcinogenesis, focused on the generation and characterization of genetically engineered animal models (Oncogene 14:1185, 1997), including characterization of the Epstein-Barr virus (EBV) ED-L2 promoter and demonstration that it is uniquely active in oral-esophageal squamous epithelial cells. This is mediated through the interaction of oral-esophageal specific nuclear transcriptional factors. These keratins are keratins 4 and 13. In fact, targeted disruption of the keratin 4 gene in murine embryonic stem cells leads to severe impairment of differentiation in esophageal epithelial cells. The EBV ED-L2 promoter is being used to target the cyclin D1 oncogene, a critical gene product in the progression of cell cycle through G1 phase, and one that is frequently amplified and overexpressed in head/neck and esophageal cancers in transgenic mice. Previous work has revealed that these mice develop histological evidence of mild dysplasia by 6-8 months and severe dysplasia by 16 months with accompanying increased cell proliferation, preferential activation of cdk6 (one target of cyclin D1/cdk6 is the retinoblastoma protein), p53 overexpression and EGFR overexpression (Cancer Res. 57:5542, 1997). P53 mutations are a common genetic alteration in head/neck and esophageal cancers. The ability to cross cyclin D1 with p53 null mice represents a unique opportunity to analyze the combinatorial effects of two critical genetic alterations in their contribution to multistage oral-esophageal carcinogenesis. The objective of this study is to utilize cyclin D1 x p53 null mice for the analysis of oral and esophageal tissues by histology, immunohistochemistry and PCR. The effects of chemopreventive agents on the development of oral and esophageal cancers in these transgenic animals is being studied.